The present invention relates to compounds that have the property of reducing serum glucose and serum triglyceride levels in diabetic mammals without the undesirable properties of reducing serum thyroxine levels and transiently raising triglyceride levels. More particularly, the present invention relates to 5,6,7,8-tetrahydronaphthalen-2-yl 2,6-difluoroheptatrienoic acid derivatives having the above-noted biological property.
Compounds that have retinoid-like activity are well known in the art, and are described in numerous United States and other patents and in scientific publications. It is generally known and accepted in the art that retinoid-like activity is useful for treating animals of the mammalian species, including humans, for curing or alleviating the symptoms and conditions of numerous diseases and conditions. It is now general knowledge in the art that two main types of retinoid receptors exist in mammals (and other organisms). The two main types or families of receptors are respectively designated the RARs and RXRs. Within each type there are subtypes; in the RAR family the subtypes are designated RARxcex1, RARxcex2 and RARxcex3, in RXR the subtypes are: RXRxcex1, RXRxcex2, and RXRxcex3. It has also been established in the art that the distribution of the two main retinoid receptor types, and of the several sub-types is not uniform in the various tissues and organs of mammalian organisms. Moreover, it is generally accepted in the art that many unwanted side effects of retinoids are mediated by one or more of the RAR receptor subtypes. Accordingly, among compounds having agonist-like activity at retinoid receptors, specificity or selectivity for one of the main types or families, and even specificity or selectivity for one or more subtypes within a family of receptors, is considered a desirable pharmacological property.
For a general overview of the retinoid receptors see Mangelsdorf et al. (1994) The Retinoid Receptors In: The Retinoids, edited by Sporn et al. p 319-349. Raven Press, Ltd., New York. For another general overview see Dawson and William H. Okamura, Chemistry and Biology of Synthetic Retinoids, published by CRC Press Inc., 1990, pages 324-356. The following further patents are of interest as background to the present invention: U.S. Pat. Nos. 5,721,103; 5,801,253; 6,326,397; PCT Publications WO 97/12853 and WO 01/19770.
Relatively recently it has become known that certain retinoid compounds are capable of reducing serum glucose levels in diabetic mammals. Mukherjee, R.; Davies, P. J.; Crombie, D. L. Bishoff, E. D.; Cesario, R. M.; Jow Hamann, L. G.; Boehm, M. F.; Mondon, C. E.; Nadzan, A. M.; Paterniti, J. R. Jr.; Heyman, R. A. Sensitization of Diabetic and Obese Mice to Insulin by Retinoid X Receptor Agonists. Nature 1997, 386(6623), 407-410. The compound (2E,4E,1xe2x80x2S, 2xe2x80x2S)-3-methyl-5-[2xe2x80x2-methyl-2xe2x80x2-(5,5,8,8-tetramethyl-5,6,7,8-tetrahydro-naphthalen-2-yl)-cyclopropyl]-penta-2,4-dienoic acid, described in U.S. Pat. No. 6,114,533, has this property. A disadvantage of the prior art retinoid compounds that reduce serum glucose levels is that their administration usually also results in the pharmacologically undesirable reduction of serum thyroxine levels and a transient increase in serum triglyceride levels. The present invention is directed to novel compounds which do not have these undesirable side effects.
The present invention relates to compounds of Formula 1
where
m is an integer having the values of 0 to 4;
n is an integer having the values of 0 or 1;
R1 is independently H, or alkyl of 1 to 6 carbons;
R2 is independently H, alkyl of 1 to 6 carbons, F, Cl, Br or I;
R3 is alkyl of 1 to 4 carbons, or CH2OR8,
R4 is alkyl of 1 to 3 carbons;
R5 is independently F or Cl;
R6 is H, F, or Cl, and
R7 is H, alkyl of 1 to 6 carbons, CH2OR or CH2OCOR8 where R8 is alkyl of 1 to 3 carbons, or a pharmaceutically acceptable salt of said compound.
The present invention also relates to pharmaceutical compositions incorporating the compounds of Formula 1 and to methods of treatment of diabetic mammals with pharmaceutical compositions containing one or more compounds of Formula 1 to reduce serum glucose levels in said mammals. The present invention also relates to the methods of using the compounds of the invention to treat diseases and conditions which are responsive to treatment by retinoids.